The role of intestinal-derived FGF15/19 during obesity and rapid weight loss
肠源性 FGF15/19 在肥胖和快速减肥过程中的作用
基本信息
- 批准号:10609823
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AdultAreaAwardAwarenessBasic ScienceBile Acid Biosynthesis PathwayBile AcidsBindingBody CompositionBody WeightBody Weight decreasedBone DensityCaloric RestrictionCardiovascular DiseasesCaringCholesterolCirculationClinical ResearchClinical SciencesCommunicationComplexDataDevelopmentDietEnterocytesEnterohepatic CirculationEnvironmentEtiologyFGF19 geneFGFR4 geneFatty LiverFibroblast Growth FactorFoundationsFutureGastrectomyGenesGlucoseGlucose ClampGoalsGreater curvature of stomachHealthHealthcareHepaticHormonesHumanHydrophobicityHyperinsulinismIn VitroInsulin ResistanceInterventionIntestinesKnockout MiceKnowledgeLeadershipLigandsLiverLiver diseasesMediatorMedical centerMentorsMentorshipMetabolicMetabolic DiseasesMichiganMorbid ObesityMusMuscular AtrophyNon-Insulin-Dependent Diabetes MellitusNuclearObesityOperative Surgical ProceduresOrganismOrthologous GeneOsteopeniaOverweightPatient SelectionPatientsPhysiologicalPhysiologyPlasmaPopulationPostdoctoral FellowPrevalenceProductionPublic HealthReceptor SignalingRegulationResearchResearch Project GrantsResourcesRiskRodent ModelRoleScientistSignal PathwaySignal TransductionSmall IntestinesTestingTherapeutic InterventionThinnessToxic effectTrainingTraining ActivityTravelUnited States Department of Veterans AffairsUniversitiesVenousVeteransWorkabsorptionbariatric surgerybone lossbone masscare burdencareer developmentcomorbiditydiagnostic tooleffective therapyexperiencefarnesoid X-activated receptorglucose metabolismglucose productionglucose toleranceglucose uptakeglycemic controlhuman diseaseileumimprovedin vivo Modelinnovationlipid metabolismliver ablationliver injuryliver metabolismmetabolomicsmilitary veteranmouse modelmuscle formnovelobese patientspatient subsetspatient variabilitypharmacologicpreclinical studypreservationpreventprogramsprotective effectreceptorresearch and developmentresponseside effectskillstranscription factorweight loss intervention
项目摘要
PROJECT SUMMARY
The prevalence of obesity among US Veterans is high and associated with a substantial healthcare burden.
The US Department of Veteran Affairs (VA) estimated 78% of Veterans are obese or overweight, which is
much higher than the estimated 35% of the non-Veteran US adult population. Bariatric surgery is currently the
most effective treatment for sustained weight loss. Bariatric surgery interventions, such as Vertical Sleeve
Gastrectomy (VSG), also improve glycemic control and other comorbidities in patients more effectively than
conventional weight loss therapies. However, with the rising use of bariatric surgery, there is also greater
awareness of its complications, such as the development of osteopenia (loss in bone mass) and liver disease
for a subset of patients. Preliminary data from our rodent model of VSG led us to hypothesize the gut hormone
Fibroblast-Growth Factor 15/19 (FGF15/19, mouse/human ortholog) as a potent mediator for VSG effects.
FGF15/19 is expressed in ileal enterocytes of the small intestine and is released postprandially in response to
bile acid absorption. Plasma FGF19 levels in humans and ileal FGF15 expression in mice greatly increased
after VSG. We sought to test whether FGF15 is also required for the effects of VSG using our novel inducible
intestine-specific FGF15 (FGF15INT-KO) mouse model. To our surprise, FGF15INT-KO VSG mice develop bone
and muscle loss after VSG. Additionally, FGF15INT-KO mice do not show improved glucose tolerance and have
increased hepatic cholesterol after VSG. The lack of FGF15 after VSG also results in markedly elevated
plasma bile acid levels, including significant increase in toxic hydrophobic bile acids. Thus, our data suggest
that increased FGF15 is essential to limit the deleterious effects of VSG by keeping bile acids within a
physiologically healthy range. The overall goal of this project is to test the hypothesis that FGF15 is a critical
regulator of enterohepatic circulation that impacts lean muscle and bone mass, hepatic lipids and glucose
metabolism after VSG. These studies propose a novel mechanism for regulating bile acid signaling in patients
who have undergone VSG and develop bone and muscle loss and liver damage. Understanding the etiology of
these complications and developing potential treatment options will improve care for VSG patients.
Dr. Bozadjieva Kramer is a Postdoctoral Research Fellow in the Department of Surgery at the University of
Michigan. She has extensive experience working with in vitro, ex vivo and in vivo models of obesity and type 2
diabetes. Dr. Randy Seeley and Dr. Robert O’Rourke at the University of Michigan will provide primary basic
science and clinical science mentorship, respectively, during the award. The career development activities will
take advantage of the exceptional research environment and resources at the University of Michigan and Ann
Arbor VA Medical Center. Dr. Bozadjieva Kramer’s career and research development will also be facilitated by
highly motivated Mentoring Committee, which includes Drs. Amy Rothberg, Ormond A. MacDougald, Charles
F. Burant and Rohit Kohli.
Dr. Bozadjieva Kramer will use various training activities to strengthen her experience, knowledge, and skills in
several areas, including technical and conceptual knowledge in clinical research and metabolomics, research
skills in rodent models of bariatric surgery, enterohepatic physiology, leadership, lab management, effective
communication, and mentoring young scientists. The training and knowledge from execution of this proposal
will lay the foundation for Dr. Bozadjieva Kramer’s future research directions in dissecting the role of
enterohepatic axis in the metabolic effects of bariatric surgery, as well as providing training for starting her own
independent research program.
项目概要
美国退伍军人中肥胖的患病率很高,并且与沉重的医疗负担有关。
美国退伍军人事务部 (VA) 估计 78% 的退伍军人肥胖或超重,这
远高于目前估计的 35% 的美国非退伍军人接受减肥手术的比例。
持续减肥的最有效治疗方法,例如垂直袖式减肥手术。
胃切除术 (VSG) 也比胃切除术更有效地改善患者的血糖控制和其他合并症
然而,随着减肥手术的使用越来越多,减肥手术也越来越多。
对其并发症的认识,例如骨质减少(骨质流失)和肝脏疾病的发生
来自我们的 VSG 啮齿动物模型的初步数据让我们勇敢地面对肠道激素。
成纤维细胞生长因子 15/19(FGF15/19,小鼠/人直系同源物)作为 VSG 效应的有效介质。
FGF15/19 在小肠的回肠肠细胞中表达,并在餐后响应
人类血浆 FGF19 水平和小鼠回肠 FGF15 表达大大增加。
VSG 后,我们试图使用我们的新型诱导剂来测试 FGF15 是否也是 VSG 效果所必需的。
肠道特异性 FGF15 (FGF15INT-KO) 小鼠模型令我们惊讶的是,FGF15INT-KO VSG 小鼠发育出骨骼。
此外,FGF15INT-KO 小鼠没有表现出葡萄糖耐量的改善,并且出现了 VSG 后的肌肉损失。
VSG 后肝脏胆固醇升高 VSG 后缺乏 FGF15 也会导致肝脏胆固醇显着升高。
血浆胆汁酸水平,包括有毒疏水性胆汁酸的显着增加,因此,我们的数据表明。
增加 FGF15 对于通过将胆汁酸保持在一定范围内来限制 VSG 的有害影响至关重要
该项目的总体目标是检验 FGF15 是一个关键的假设。
影响瘦肌肉和骨量、肝脂和葡萄糖的肠肝循环调节剂
这些研究提出了一种调节患者胆汁酸信号传导的新机制。
接受 VSG 并出现骨骼和肌肉损失以及肝损伤的患者 了解其病因。
这些并发症和潜在的治疗方案将改善 VSG 患者的护理。
Bozadjieva Kramer 博士是莫斯科大学外科系的博士后研究员
她在肥胖和 2 型的体外、离体和体内模型方面拥有丰富的经验。
密歇根大学的 Randy Seeley 博士和 Robert O’Rourke 博士将提供初级基础知识。
颁奖期间将分别提供科学和临床科学指导。
利用密歇根大学和安大学卓越的研究环境和资源
Arbor VA 医疗中心也将促进 Bozadjieva Kramer 博士的职业生涯和研究发展。
积极主动的指导委员会,包括 Amy Rothberg 博士、Ormond A. MacDougald 博士、Charles 博士
F. Burant 和罗希特·科利。
Bozadjieva Kramer 博士将利用各种培训活动来加强她在以下方面的经验、知识和技能:
多个领域,包括临床研究和代谢组学、研究中的技术和概念知识
减肥手术啮齿动物模型、肠肝生理学、领导力、实验室管理、有效的技能
沟通,并指导年轻科学家执行该提案的培训和知识。
将为 Bozadjieva Kramer 博士未来的研究方向奠定基础,剖析
肠肝轴在减肥手术代谢影响中的作用,并为她开始自己的手术提供培训
独立研究计划。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nadejda Bozadjieva Kramer其他文献
Nadejda Bozadjieva Kramer的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nadejda Bozadjieva Kramer', 18)}}的其他基金
The role of intestinal-derived FGF15/19 during obesity and rapid weight loss
肠源性 FGF15/19 在肥胖和快速减肥过程中的作用
- 批准号:
10364480 - 财政年份:2022
- 资助金额:
-- - 项目类别:
相似国自然基金
开发区跨界合作网络的形成机理与区域效应:以三大城市群为例
- 批准号:42301183
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
秦岭生态效益转化与区域绿色发展模式
- 批准号:72349001
- 批准年份:2023
- 资助金额:200 万元
- 项目类别:专项基金项目
我国西南地区节点城市在次区域跨国城市网络中的地位、功能和能级提升研究
- 批准号:72364037
- 批准年份:2023
- 资助金额:28 万元
- 项目类别:地区科学基金项目
通过自主研发的AAV8-TBG-LOX-1基因治疗技术祛除支架区域氧化型低密度脂蛋白抑制支架内新生动脉粥样硬化研究
- 批准号:82370348
- 批准年份:2023
- 资助金额:47 万元
- 项目类别:面上项目
政府数据开放与资本跨区域流动:影响机理与经济后果
- 批准号:72302091
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Understanding how exocrine-derived signals promote beta cell growth
了解外分泌信号如何促进 β 细胞生长
- 批准号:
10750765 - 财政年份:2024
- 资助金额:
-- - 项目类别:
A Paradigm Shift in Health Behavior Change: Understanding When and How Social Comparison Supports Healthy Behavior
健康行为改变的范式转变:了解社会比较何时以及如何支持健康行为
- 批准号:
10685733 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Characterizing the genetic etiology of delayed puberty with integrative genomic techniques
利用综合基因组技术表征青春期延迟的遗传病因
- 批准号:
10663605 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Investigating the role of public transit on health behaviors among older adults with disabilities
调查公共交通对残疾老年人健康行为的作用
- 批准号:
10644067 - 财政年份:2023
- 资助金额:
-- - 项目类别: